Improvements in vaccines against influenza that increase potency, breadth and duration of protection would improve worldwide ability to combat seasonal changes in influenza viruses (drift) and emergence of new pandemic strains (shift). This study aims to develop new platforms and vaccination strategies against influenza. Nanoparticle-, and nucleic acid-based vaccines have been developed against multiple seasonal and pandemic strains of influenza, including H7N9, and H5N1 avian influenza viruses. In addition, studies are ongoing to identify and optimize vaccine antigens to present conserved regions of the influenza virus hemagglutinin (HA) in order to develop a vaccine that provides broader universal protection. These include nanoparticle display of both group 1 and group 2 influenza HA stabilized stem trimers, as well as a collection of less-conserved HA head domains. Testing has been conducted to evaluate candidates, as well as adjuvants to boost immune response, and determine the optimal strategies for immunization. Several candidates showed promising results that lead to further evaluations, using DNA and DNA prime with inactivated vaccine boost or nanoparticles displaying full length, stem, and/or receptor-binding domain HA antigens. Multiple cycles of iterative structure-based design yielded a structurally stabilized trimer of the HA stem derived from H1N1 A/New Caledonia/20/1999, which belongs to group 1. Several versions of these immunogens were generated and tested its immunogenicity in animal models, as well as to co-crystallize with stem-binding monoclonal antibodies. Immunization with these nanoparticles induces homologous and heterologous binding antibodies in mice and ferrets with low levels of neutralizing antibodies. Despite this relatively weak neutralizing activity, immunization confers complete protection in mice and near-complete protection in ferrets from heterosubtypic H5N1 lethal influenza challenge. Passive transfer of immunoglobulins from immunized mice provides protection against lethal H5 challenge in recipient mice, indicating the protection is antibody-mediated. Further studies to determine the immunological basis of protection are underway, as well as efforts to improve the group 1 immunogen to increase neutralizing responses. Group 2 designs have also been advanced through in vitro characterizations, animal studies and product development, and a lead candidate is now in GMP manufacturing. In addition, collaborations to develop gene-based vaccine platforms such as mRNA platform are underway. The first-in-human influenza HA nanoparticle vaccine clinical trial is nearly complete, and the Phase 1 clinical trial testing the H1 stem ferritin immunogen is currently enrolling. The Phase 1 trial utilizing the group 2 stem immunogen is expected to open in spring 2020. Collaborations have been established to design novel multi-component nanoparticles, and the first candidate shows promising immunogenicity results in animal models and is being transferred into advanced product development. The design program utilizing viral neuraminidase (NA) initiated last year continues, with progress made on reagents, assays, and candidate immunogens for testing in animal models. Collaborations are in progress to pair vaccine candidates with advanced adjuvants in Phase 1 clinical trials.